1. Field of the Invention
The present invention relates to a novel process for producing nucleic acid derivatives and in particular to an industrially useful process for reducing sugar-moiety hydroxyl groups and halogen atoms in nucleic acids and their derivatives (their related compounds etc.).
According to the present invention, an intermediate for producing various pharmaceutical preparations, for example an intermediate for producing 9-(2,3-dideoxy-2-fluoro-xcex2-D-threo-pentofuranosyl) adenine (also may be called xe2x80x9cFddAxe2x80x9d as the abbreviation in the specification) and 2xe2x80x2,3xe2x80x2-dideoxyadenosine (also may be called xe2x80x9cddAxe2x80x9d as the abbreviation in the specification) useful as antiviral agents can be produced industrially advantageously.
2. Description of the Related Art
For dehydroxylation (deoxylation) of sugar-moiety hydroxyl groups in nucleic acids or in their related compounds, the method of radically reducing thiocarbonyl derivatives of such hydroxyl groups has been generally used. Further, for dehalogenation of sugar-moiety halogen atoms in nucleic acids or in their related compounds, the method of radically reducing them has been generally used (for example, see A. G. Sutherland, xe2x80x9cComprehensive Organic Functional Group Transformationsxe2x80x9d, Vol. 1, A. R. Katritzky, et al., Ed., Pergamon, London, pp. 1-25).
In the radical reduction described above, tin compounds such as tributyl tin hydride are used most generally as radical reducing agents. However, tin compounds when used in industrial production are problematic in their toxicity during operation, and when used in production of pharmaceutical preparations etc., their presence even in a trace amount is not allowable and their use is virtually not possible. Silyl hydride-type compounds such as tris (trimethylsilyl) silane are used as radical reducing agents in some cases, but these silyl hydride-type compounds are generally not produced in industrial scale, and even if produced, they are very expensive and very difficult to use in industry.
In recent years, Barton et al. conducted radical reduction of thiocarbonyl derivatives and halogen atoms with hypophosphorous acid or salts thereof or with esters of phosphorous acid (for example, see D. H. R. Barton, et al., Tetrahedron Lett., 33(39), 5709 (1992) and D. H. R. Barton, et al., J. Org. Chem., 58, 6838 (1993)). However, these literatures illustrate the radical reduction of only simple hydrocarbons or sugar derivatives having a few functional groups, and whether this radical reduction can be applied to complex heterocyclic nucleic acid derivatives was not known.
Accordingly, there is a need for an industrially advantageous and safe process applicable widely to nucleic acid derivatives in order to produce the reduced compound.
The object of the present invention is to establish an industrially useful and highly safe process for producing the reduced compounds at low costs, wherein sugar-moiety hydroxyl groups and halogen atoms in nucleic acids or in their derivatives (including their related compounds etc.) can be selectively reduced to advantageously produce a wide variety of useful nucleic acid derivatives such as intermediates for producing the active ingredients (FddA, ddA etc.) in pharmaceutical preparations.
As a result of their eager study to solve the problem described above, the present inventors found that compounds wherein sugar-moiety hydroxyl groups or halogen atoms in nucleic acids and derivatives thereof (referred to collectively as xe2x80x9cnucleic acid derivativesxe2x80x9d) have been reduced can be easily obtained by allowing O-thiocarbonyl derivatives of sugar-moiety hydroxyl groups, or halogenated derivatives in the sugar-moiety thereof, to react with any one of hypophosphorous acids (including salts thereof) and esters of phosphorous acid which are inexpensive, non-toxic and safely usable as radical reducing agents in industrial scale, in the presence of a radical reaction initiator, and as a result, the present inventors found that it is thereby possible to derive a wide variety of useful nucleic acid derivatives industrially efficiently, to arrive at the completion of the present invention.
That is, the present invention encompasses the following inventions.
(i) A process for producing a nucleic acid derivative represented by the general formula (II): 
wherein B represents a nucleic acid base, R represents a hydrogen atom or a hydroxy group-protecting group, and one of Yxe2x80x2 and Xxe2x80x2 represents a hydrogen atom and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, which comprises allowing a nucleic acid derivative having an eliminating group represented by the general formula (I): 
wherein B and R have the same meanings as defined above, and one of Y and X represents an eliminating group and the other represents a hydrogen atom, a fluorine atom, a hydroxyl group or a protected hydroxyl group, respectively, to react with at least one compound selected from hypophosphorous acid (including salts thereof) and esters of phosphorous acid in the presence of a radical reaction initiator. In this reaction, the above eliminating group is reduced and converted into a hydrogen atom.
In the present invention, the nucleic acid base represented by the above group B also includes nucleic acid base derivatives. The nucleic acid base derivatives include e.g. N-acetylguanine, N-acetyladenine, N-benzoylguanine, N-benzoyladenine, 2-amino-6-chloropurine and 6-chloropurine.
(ii) The process according to item (i) above, wherein B is a purine base or a pyrimidine base or a derivative thereof.
(iii) The process according to any one of the above items, wherein B is any one of hypoxanthine, adenine, guanine, uracil, thymine and cytosine, or a derivative thereof.
(iv) The process according to item (i) above, wherein R is any one of a hydrogen atom, an acyl group, an alkyl group, an aralkyl group and a silyl group.
(v) The process according to any one of the above items, wherein R is any one of a hydrogen atom, an acetyl group, a benzoyl group and a trityl group.
(vi) The process according to any one of the above items, wherein the eliminating group is either a halogen atom excluding a fluorine atom or an O-thiocarbonyl derivative (residue).
The halogen atom includes the respective atoms of chlorine, bromine and iodine, and the O-thiocarbonyl derivative (residue) includes O-phenoxythiocarbonyl group: PhO(Cxe2x95x90S)Oxe2x80x94, O-parafluorophenoxythiocarbonyl group: p-Fxe2x80x94PhO(Cxe2x95x90S)Oxe2x80x94, O-methylthiothiocarbonyl group: MeS(Cxe2x95x90S)Oxe2x80x94, O-phenylthiothiocarbonyl group: PhS(Cxe2x95x90S)Oxe2x80x94, and O-imidazolylthiocarbonyl group: 
(vii) The process according to any one of the above items, wherein one of Y and X is an eliminating group and the other is any one of a hydroxyl group, an acyloxy group, an alkyloxy group, an aralkyloxy group and a silyloxy group.
(viii) The process according to any one of the above items, wherein one of Y and X is an eliminating group and the other is any one of a hydroxyl group, an acetyloxy group and a benzoyloxy group.
(ix) The process according to any one of the above items, wherein hypophosphorous acid is in the form of sodium hypophosphite.
(x) The process according to item (i) above, wherein the radical reaction initiator is an azo compound.
The azo compound is preferably an azonitrile compound, an azoamidine compound, a cyclic azoamidine compound, an azoamide compound, an alkyl azo compound etc. Specific individual compounds contained in these respective compounds include compounds known to be contained in these compounds, but may be compounds to be found in the future.
(xi) The process according to any one of the above items, wherein the compound produced in the above process wherein B is a purine base or a derivative thereof, Yxe2x80x2 is a hydrogen atom, Xxe2x80x2 is a hydroxyl group or a protected hydroxyl group, is subjected to at least one step selected from the step deprotecting the hydroxyl group, the step of halogenation at the 6-position, the step of amination at the 6-position and the step of fluorination at the 2xe2x80x2-position to produce FddA.
(xii) A process for producing a derivative substituted with a halogen at the 6-position, wherein the nucleic acid derivative of the general formula (II) obtained above wherein B is 6-hydroxypurine is halogenated selectively at the 6-position with a halogenating agent for example a chlorinating agent of a combination of phosphorus oxychloride and N,N-dimethylaniline or sulfuryl chloride and dimethylformamide or a chlorinating agent such as dimethyl chloromethylene ammonium chloride and if necessary the product is subjected to the step of deprotection, to produce the derivative halogenated at the 6-position.
(xiii) A process for producing FddA, wherein the derivative halogenated at the 6-position obtained above is further subjected to a method of replacing the halogen atom by an amino group (ammonia treatment etc.) and a method of substituting the 2-position with fluorine (treatment with diethylaminosulfur trifluoride, morpholinosulfur trifluoride, or etc.) in this order or in the reverse order and as necessary the product is subjected to the step of deprotection to produce FddA.
(xiv) A process for producing ddA, wherein the nucleic acid derivative of the general formula (II) obtained above wherein B is adenine and Yxe2x80x2 and Xxe2x80x2 are hydrogen atoms is subjected to the step of deprotecting the hydroxyl group with an acid or an alkali as necessary to produce ddA.